Advanced Glycation Endproducts Promote Adhesion Molecule (VCAM-1, ICAM-1) Expression and Atheroma Formation in Normal Rabbits (original) (raw)

Abstract

Background

Reactive glucose-protein intermediates and advanced glycation endproducts (AGEs) are shown to colocalize with atheromatous lesions and to trigger complex chemical and biological responses through interaction with vessel wall elements. In diabetes and renal insufficiency, atherosclerosis is common, as are elevated levels of serum and vascular tissue AGEs. In the present study, AGEs supplied exogenously to normal animals elicited vascular and renal pathology.

Materials and Methods

Nondiabetic rabbits were injected intravenously with low doses of AGE-modified rabbit serum albumin (AGE-RSA, 16 mg/kg/day) for 4 months alone, or combined with a brief terminal period (2 weeks) of a cholesterol-rich diet (CRD) (2% cholesterol, 10% corn oil). AGE-RSA associated expression of vascular cell adhesion molecules and the development of atheromatous changes within the aorta were determined by immunohistology.

Results

The AGE content of aortic tissue increased by 2.2-fold in AGE-treated and by 3.2-fold in AGE + CRD-treated rabbits compared with normal saline-treated control rabbits (p < 0.025 and 0.001, respectively). Serum AGE levels in AGE groups rose up to 3-fold above the controls (p < 0.025 and p < 0.01). Ascending aortic sections from AGE-treated rabbits showed significant focal intimal proliferation, enhanced endothelial cell adhesion with infrequent intimal macrophages, oil-red-O staining lipid deposits and positive focal expression of vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), a pattern not observed in controls. These AGE-induced changes were markedly enhanced in animals cotreated with AGEs and a brief period of CRD. Lesions consisted of multifocal atheromas, containing foam cells, massive lipid droplets, and strong endothelial expression of VCAM-1 and ICAM-1 restricted to the affected areas.

Conclusions

This study provides in vivo evidence for a causal relationship between chronic AGE accumulation and atherosclerosis independent of diabetic hyperglycemia, and suggests the utility of this animal model for the study of diabetic vascular disease in relation to glycation.

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Acknowledgments

We would like to thank Dr. Kirk Manogue for his valuable guidance and to Ms. Donna Bove for her editorial assistance. These studies were supported in part by The National Institutes of Health Grants AGO-6943 and AGO-9453 (to HV) and HL 45563 (MC).

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Authors and Affiliations

  1. The Picower Institute for Medical Research, 350 Community Drive, Manhasset, New York, 11030, USA
    Helen Vlassara, Hubert Fuh & Thomas Donnelly
  2. Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts, USA
    Myron Cybulsky

Authors

  1. Helen Vlassara
  2. Hubert Fuh
  3. Thomas Donnelly
  4. Myron Cybulsky

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Vlassara, H., Fuh, H., Donnelly, T. et al. Advanced Glycation Endproducts Promote Adhesion Molecule (VCAM-1, ICAM-1) Expression and Atheroma Formation in Normal Rabbits.Mol Med 1, 447–456 (1995). https://doi.org/10.1007/BF03401582

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